Research Program

Summary:

Our research program has focused on
understanding the functional and structural impacts of segmental
duplications on the human genome. Using computational and
experimental approaches, we have investigated duplications at a genomic
rather than strictly at the genic level. Our research has
challenged the field of vertebrate genome evolution which largely held
that “most of nature’s experiments with duplication must have been done
at the stages of fish and amphibians”. Within the
genetics and evolutionary community, this has led to a resurgence of
interest in genomic duplications and series of unanswered
questions: How did this complex architecture of duplications
evolve in humans? What is the underlying mechanism? How
variable are these regions within the human population and to what
extent do they contribute to disease and phenotypic differences?
How does the human structure compare to that of great apes and other
mammals? Have new genes
evolved by this mechanism which are important for human/great ape
adaptation? Our research program is committed to addressing these
questions. We summarize below some of our major contributions to
this field.

Human genome duplication
architecture: We provided the first global view of
segmental duplications within the human genome and showed that they
account for ~5% of the genome. We developed a computational pipeline
that utilizes
whole-genome shotgun sequences as a means to detect duplications
independently from a whole-genome assembly. We used this
information to develop a road-map of likely sites of recurrent
chromosomal structural rearrangement and rapid evolutionary
change. The relationship of these regions with human disease is
an active area of investigation.

Pericentromeric Model: We developed a donor-acceptor
model for the origin and spread of segmental duplications based on
detailed study of a subset of hotspot regions near the pericentromeric
regions of human chromosomes. The data indicate
that euchromatic genomic segments ranging in length from 5-150 Kb have
been preferentially integrated near pericentromeric DNA, that specific
low complexity repeat sequences serve as preferred sites for
integration and that these segments transposed to these regions very
recently (1-15 Mya) through a complex series of events.

Genome assembly quality and validation. We
developed experimental and computational approaches to resolve these
problematic regions of the genome and applied these tools to improving
single nucleotide polymorphism assignment and genome assembly in these
regions. These same approaches are now being applied to
other mammalian genomes to understand their genomic duplication
properties in spite of assembly issues.

Comparative Primate Genomics and Adaptive Evolution.
We have documented some of the first quantitative and qualitative
differences in the distribution of segmental duplication among the
genomes of humans and the great-apes. We have discovered some of the
most rapidly evolving gene families within these duplications and
demonstrate that ~12% of all expression differences between human and
chimpanzee brains occur within segmental
duplications.

Alu- mediated duplicative Transposition: We
systemically examined the sequence features at duplication junctions
and showed an enrichment of Alu short interspersed
repeat sequences near the edges. We propose that the primate-specific
burst of Alu retroposition activity (which occurred ~40 million years
ago) sensitized the ancestral human genome for Alu-Alu-mediated
recombination events, which, in turn, initiated the expansion of
gene-rich segmental duplications.

Non-random Chromosomal Rearrangement. A
comparison between sites of segmental duplication and breakpoints in
regions with conserved synteny between man and mouse showed that ~30%
of all synteny breaks mapped to clusters of segmental duplication. We
noted a similar association when human and
primate genomes were compared.
These data suggest hotspots
or fragile sites of chromosomal breakage and challenge the
Nadeau-Taylor random breakage model of chromosomal evolution.